Headache is one of the most frequent complaints attributed to environmental air pollution (indoor and outdoor), but the total impact on public health is difficult to quantify. Increased exposure to chemical irritants in the air we breathe may be responsible for the increased incidence of migraine as well as more recently described disorders such as Sick building syndrome (SBS) and Multiple chemical sensitivity (MCS). The most common complaint in patients suffering SBS or MCS is headache and both disorders have been linked to exposure to chemical irritants. In recent years, a new molecular target for diverse chemical structures, including several components of environmental irritants, has emerged. It has been demonstrated that a member of the transient receptor potential (TRP) superfamily of ligand-gated ion channels, TRPA1, is activated by a novel mechanism involving covalent interaction between many chemicals and the receptor-channel leading to excitation of sensory neurons expressing TRPA1 and elevations in intracellular calcium. In this proposal, we will examine a specific hypothesis linking inhaled chemical irritants to the induction of headache symptoms. We propose that chemical activation of TRPA1 homomers, or TRPA1/TRPV1 heteromers on trigeminal neurons innervating the meninges results in release of calcitonin gene-related peptide (CGRP), a potent vasodilator implicated in migraine. The resultant vasodilatation provokes headache symptoms. To examine this hypothesis, we address three specific aims using a combination of approaches in a rodent model: (1) Examination of whether TRPA1 in trigeminal neurons innervating the dura is involved in stimulating meningeal blood flow by nasally administered chemical irritants. (2) Determination of the role of CGRP release in the dura in mediating increased meningeal blood flow induced by chemical irritants. (3) Determination of the relative roles of TRPA1 and TRPV1 in mediating chemical irritant induced responses in trigeminal neurons and of meningeal blood flow. Our experiments will combine Laser Doppler flowmetry, measurements of CGRP release, fluorescence imaging of intracellular calcium, cellular electrophysiology, biochemistry, gene knock-out mice for TRPA1 or TRPV1, and pharmacological and molecular interference to address these issues. Understanding how headache is provoked by chemical irritants is an important question in environmental health with the potential for a significant impact on public health. PUBLIC HEALTH RELEVANCE: Pollution related health issues are becoming more prevalent and creating a significant societal and economic burden. Headache is the most common symptom associated with indoor and outdoor air pollution but how environmental irritants, such as formaldehyde and acrolein, cause headache is not known. Sick Building Syndrome and Multiple Chemical Sensitivity, disorders associated with environmental irritants may have similar mechanistic bases as migraine, a common headache disorder. The pain associated with migraine is thought to be due to activation of the trigeminal sensory neurons which synapse on the cerebral blood vessels, the trigeminovascular system. The goal of the proposed studies is to determine whether environmental irritants activate the trigeminovascular system via binding to chemical sensing receptors known as TRP channels.